A major hypothesis of this Program Project Grant is that intrauterine stresses can modify the program governing cell growth in adult life by dysregulating proliferative/hypertrophic signals within the heart. Understanding the signaling pathways that couple intrauterine stresses to cardiac growth are directly relevant to the overall goal of this PPG. We propose that selectively manipulating the proliferative and hypertrophic signals within the developing cardiomyocyte will provide an animal model of pathophysiological consequences of altered cardiac cell growth. We will establish genetic models in mice to test this hypothesis. The hypothesis to be tested in this proposal is that modifying hypertrophic and proliferative pathways converge to mediate the growth response in the heart. Studies by Kent Thornburg and co-workers have shown a requirement for extracellular signal-regulated kinase (ERK) and phosphoinositol-3 kinase (PI3-K) in the hyperplastic response of sheep myocardial cells to IGF. Recent studies suggest that PI3-K and ERK signals can also converge on hypertrophic signals via the mTOR pathway that regulates protein translation and growth. Importantly this pathway is also influenced by PI3-K and ERK signaling pathways. One of the major targets of mTOR action, the ribosomal p70 S6 kinase (S6K), is activated by both by PI3-K and ERK signaling pathways. We propose that activation of the mTOR pathway is sufficient for hypertrophy, and that both mTOR and ERKs are necessary for full hypertrophic response to developmental stresses. We predict that constitutive activation of the PI3-K/mTOR cascade is sufficient for cardiac hypertrophy and that both PI3-K/mTOR and ERK pathways are necessary for cardiac hypertrophy. This will be tested in three specific aims using genetically modified animal models of cardiac function.